Abstract 17166: Myeloid-specific Deletion of the Glucocorticoid Receptor Increases Mitochondrial Oxidative Stress and Impairs Wound Healing After Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jonas Neuser ◽  
Daniela Fraccarollo ◽  
Jan P Tuckermann ◽  
Paolo Galuppo ◽  
Johann Bauersachs
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Wound Healing ◽  
Glucocorticoid Receptor ◽  
Mononuclear Cells ◽  
Flow Cytometric Analysis ◽  
Myeloid Cells ◽  
Coronary Artery Ligation ◽  
Mitochondrial Oxidative Stress ◽  
Specific Deletion

Background: Glucocorticoid administration impairs ischemic wound healing by inhibiting inflammation and angiogenesis via a glucocorticoid receptor (GR)-mediated transcriptional response. However, there are also apparently contradictory reports claiming protective effects of glucorticoid administration after myocardial infarction (MI). We investigated the role of the GR in myeloid cells for infarct wound healing, using GR deficient mice (GRLysMCre). Methods and Results: MI was induced by permanent left coronary artery ligation in GRflox (wild-type [WT] controls) and GRLysMCre mice. The 7-day mortality was significantly lower in WT compared with GRLysMCre mice. At 7 days post MI, GRLysMCre mice exhibited significantly enhanced thinning and dilatation of the infarcted wall, LV chamber enlargement and functional deterioration. This was associated with altered granulation tissue formation and impaired neoangiogenesis at the site of ischemic injury. Multicolor flow cytometric analysis and immunohistochemical studies revealed at the 2nd day post infarction less infiltrating mononuclear cells [CD11bhigh and (CD49b, NK1.1, B220, CD90, Ly6G)low] in the healing myocardium of GRLysMCre mice. Mononuclear cells were identified as monocytes (F4/80, I-Ab, CD11c)low and as macrophages/dendritic cells (F4/80, I-Ab, CD11c)high. Monocytes lacking GR, isolated from peripheral blood and spleen by magnetic-activated cell sorting 1 day after MI, displayed reduced migration capacity and increased superoxide anion production in mitochondria, which was detected by HPLC-electrochemical analysis of Mito-2-hydroxy-E+. Moreover, at day 2 and 3 we found enhanced cellular and mitochondrial oxidative stress in the healing myocardium of GRLysMCre mice. Conclusions: Myeloid-specific deletion of the GR increasing mitochondrial oxidative stress alters wound healing and promotes infarct expansion. Our results suggest that the GR in myeloid cells play a crucial role during cardiac repair after myocardial infarction.

scholarly journals Quantitative and qualitative composition of the innate immune response are equally important in wound healing after myocardial infarction

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
J Wrobel ◽  
J Rettkowski ◽  
H Seung ◽  
C Wadle ◽  
P Stachon ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Cycle ◽  
Wound Healing ◽  
Innate Immunity ◽  
Cardiac Function ◽  
Ventricular Remodeling ◽  
Myeloid Cells ◽  
Fold Increase ◽  
Remote Myocardium ◽  
Inflammatory Phenotype

Abstract Background Emergency hematopoiesis (EH) serves as the foundation of monocyte-derived and macrophage (Mφ) driven efferocytosis and ventricular remodeling after myocardial infarction (MI). Excessive myelopoiesis, however, can stipulate maladaptive wound healing and its therapeutic reduction may be a novel approach to preserve cardiac function. All-trans retinoic acid (ATRA) is a pleiotropic modulator of EH and innate immunity shielding hematopoietic stem cells from activation and driving survival and differentiation of myeloid cells. Purpose This study aimed to investigate this intriguing interplay of ATRA in wound healing after MI. Methods MI was induced by permanent coronary ligation in C57BL/6 mice and treated with daily injections of either ATRA (30mg/kg) or DMSO (vehicle) up to five days, starting 24h after ligation. Flow cytometry (FACS) was used for cell cycle analysis and immunophenotyping of leukocytes in bone marrow (BM), blood and heart. Immunohistochemistry (IH), masson trichrome (MT) staining and echocardiography evaluated inflammatory-fibrotic and functional development. Cytokine expression was analyzed by qPCR in bulk infarct and isolated, polarized Mφ-populations of BM-derived and cardiac resident origin. Results On day 2 after MI, EH was significantly reduced in ATRA-treated mice as compared to vehicle controls by means of cell cycle activity (n=6–13 per group; p<0,01) and myeloid cells in BM, blood and infarct tissue (n=5–13; p<0,05). Consequently, mRNA-expression of key inflammatory cytokines, IL-1β and TNFα, was diminished in the infarct tissue in this early phase (n=5–12; p<0,05). These changes, however, failed to preserve cardiac function and ventricular remodeling, 21 days after MI (n=10–11; not significant). By qPCR, non-canonical activation of recruited ATRA-primed monocyte-derived Mφ, was found to propagate a pro-inflammatory phenotype with higher expression of MMP2 and MMP9 in sorted cardiac Mφ (n=4–5; p<0,001). Furthermore, prominent IL-1β-expression in M2-polarized BM-derived Mφ indicated an impaired anti-inflammatory phenotype after ATRA treatment (n=4–6; p<0,05). Strikingly, these changes also occurred in remote myocardium where IH revealed a 2-fold increase of CD11b - positive myeloid cells accompanied by increased expression of TNFα and TGFβ (n=9; p<0,001). MT-staining, performed 21 days after MI, demonstrated an almost 3-fold increase in collagen deposition in remote myocardium of ATRA treated mice in contrast to vehicle controls (n=4–6; p<0,0001). Conclusion Despite a beneficial reduction of EH after MI, short-term treatment with ATRA induced profound and persisting changes in the cytokine expression of monocyte-derived Mφ, which significantly altered their function and thus prevented improvements in cardiac function. Our data provide evidence that quantitative and qualitative changes in innate immunity are equally important for cardiac remodeling after MI. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft

scholarly journals PO-173 The Effects of Interval Exercise on oxidative stress and Smyd1-related myocardial hypertrophy in Rats with Myocardial Infarction

2018 ◽  
Vol 1 (4) ◽  
Author(s):  
Qiaoqin Liang ◽  
Mengxin Cai ◽  
Jiaqi Zhang ◽  
Zhenjun Tian
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Cardiac Function ◽  
Stress Level ◽  
Exercise Group ◽  
Control Group ◽  
Coronary Artery Ligation ◽  
Interval Exercise ◽  
Oxidative Stress Level ◽  
Sarcomere Assembly

Objective This study was carried out to investigate interval exercise on Smyd1 expression and F-actin sarcomere assembly in non-infarcted myocardium of normal and myocardial infarction(MI) rats and its possible mechanism. Methods Male SD rats were randomly divided into normal control group (C), normal interval exercise group (CE), sham-operated group (S), MI group (MI), MI with interval exercise group (ME) and MI with ROS Tempol group (MT), n=10. MI model was established by left anterior descending coronary artery ligation. Interval exercise was carried out on a small animal treadmill. MT group was given an oral solution of Tempol (2mmol/L). Hemodynamics was performed to evaluate cardiac function. HE and Masson staining were used to analyze the cross-sectional area (CSA) of cardiomyocytes and collagen volume fraction, respectively. T-SOD and MDA kits were used to detect oxidative stress. H9C2 cells were treated with H2O2. Immunofluorescence staining was used to determine Smyd1 expression and F-actin sarcomere assembly. RT-qPCR and Western blotting were used to detect the gene or protein expression of Smyd1, Trx1, Hsp90, MuRF1, cTnI, α-actinin and BNP. Results Smyd1, Trx1, Hsp90, MuRF1 and BNP expression in the peri-infarcted area were up-regulated, but cTnI and α-actinin expression and F-actin assembly were decreased. The cardiac function was reduced. Both interval exercise and Tempol intervention significantly increase the CSA and expression of Smyd1, Trx1, cTnI and α-actinin, improve the antioxidation capacity and F-actin sarcomere assembly and cardiac function, reduce the expression of Hsp90, MuRF1, BNP and ROS level, and inhibit the fibrosis of myocardium. The oxidative stress level was closely related to the Smyd1 expression. Improvement of cardiac function were correlated with Smyd1 expression. H2O2 can induce oxidative stress injuries of H9C2, and its closely related to cardiomyocytes oxidative stress level and Smyd1 expression. Conclusions Interval exercise could promote antioxidant capability and physiological cardiomyocyte hypertrophy, regulate the expression of Smyd1, Hsp90 and MuRF1 in infarcted heart; so as to improve the cardiac function. Smyd1 may participate in pathologic hypertrophy of cardiomyocytes caused by oxidative stress.

Preventive effects of zingerone on cardiac mitochondrial oxidative stress, calcium ion overload and adenosine triphosphate depletion in isoproterenol induced myocardial infarcted rats

RSC Advances ◽  
2016 ◽  
Vol 6 (113) ◽  
pp. 112332-112339 ◽  
Author(s):  
Kunchpillai Lakshmanan Hemalatha ◽  
Ponnian Stanely Mainzen Prince
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Adenosine Triphosphate ◽  
Calcium Ion ◽  
Atp Depletion ◽  
Mitochondrial Oxidative Stress ◽  
Preventive Effects

Cardiac mitochondrial oxidative stress, calcium ion (Ca2+) overload and adenosine triphosphate (ATP) depletion play an important role in the pathogenesis of myocardial infarction.

Abstract P274: Cardiac-Specific Knockout of Capn4 Attenuates Myocardial Remodeling and Improves Function After Myocardial Infarction in Mice

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Jian Ma ◽  
Meng Wei ◽  
Hao Wang ◽  
Weihua Liu ◽  
Wei Zhu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Mouse Model ◽  
Coronary Artery Ligation ◽  
Down Regulation ◽  
Artery Ligation ◽  
Cardiac Apoptosis ◽  
Myocardial Remodelling ◽  
Calpain 2 ◽  
Specific Deletion

Background - Calpain has been implicated in myocardial injury after myocardial infarction (MI). However, no direct evidence is available on the role of calpain in post-MI myocardial remodelling and dysfunction. The present study investigated the effects of cardiomyocyte-specific deletion of Capn4 , essential for calpain-1 and calpain-2 activities on myocardial remodelling and dysfunction following MI. Methods and Results - A novel mouse model with cardiomyocyte-specific deletion of Capn4 ( Capn4-ko ) was generated. MI was induced by left coronary artery ligation. Deficiency of Capn4 significantly reduced the protein levels and activities of calpain-1 and calpain-2 in the Capn4-ko heart. In vivo cardiac function was relatively improved in Capn4-ko mice at 7 and 30 days after MI compared with their wild-type littermates. Deletion of Capn4 reduced cardiac apoptosis, limited infarct expansion and infarct zone thinning, and prevented left ventricle dilation in Capn4-ko mice. Furthermore, myocardial collagen deposition and cardiomyocyte cross-sectional areas were significantly attenuated in Capn4-ko mice, which were accompanied by down-regulation of pro-fibrotic genes and hypertrophic genes. These effects of Capn4 knockout correlated with down-regulation of inflammatory mediators and normalization of matrix metalloproteinase (MMP)-9 activity in the non-infarct area of Capn4-ko mice after MI. In vivo mouse model of endotoxemia confirmed that calpain activation resulted in inflammatory gene expression and MMP-9 activity in the heart. Conclusions - Cardiomyocyte-specific knockout of calpain attenuates myocardial adverse remodelling and improves myocardial function after MI. These beneficial effects of calpain disruption may result from inhibition of cardiac apoptosis, inflammation and MMP-9 activity.

scholarly journals Aucubin Protects against Myocardial Infarction-Induced Cardiac Remodeling via nNOS/NO-Regulated Oxidative Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Zheng Yang ◽  
Qing-Qing Wu ◽  
Yang Xiao ◽  
Ming Xia Duan ◽  
Chen Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Coronary Artery Ligation ◽  
No Production ◽  
Protective Effects ◽  
Artery Ligation ◽  
Nos Inhibitors

Whether aucubin could protect myocardial infarction- (MI-) induced cardiac remodeling is not clear. In this study, in a mouse model, cardiac remodeling was induced by left anterior descending coronary artery ligation surgery. Mice were intraperitoneally injected with aucubin (10 mg/kg) 3 days post-MI. Two weeks post-MI, mice in the aucubin treatment group showed decreased mortality, decreased infarct size, and improved cardiac function. Aucubin also decreased cardiac remodeling post-MI. Consistently, aucubin protected cardiomyocytes against hypoxic injury in vitro. Mechanistically, we found that aucubin inhibited the ASK1/JNK signaling. These effects were abolished by the JNK activator. Moreover, we found that the oxidative stress was attenuated in both in vivo aucubin-treated mice heart and in vitro-treated cardiomyocytes, which caused decreased thioredoxin (Trx) consumption, leading to ASK1 forming the inactive complex with Trx. Aucubin increased nNOS-derived NO production in vivo and vitro. The protective effects of aucubin were reversed by the NOS inhibitors L-NAME and L-VINO in vitro. Furthermore, nNOS knockout mice also reversed the protective effects of aucubin on cardiac remodeling. Taken together, aucubin protects against cardiac remodeling post-MI through activation of the nNOS/NO pathway, which subsequently attenuates the ROS production, increases Trx preservation, and leads to inhibition of the ASK1/JNK pathway.

scholarly journals Scavenging superoxide selectively in mouse forebrain is associated with improved cardiac function and survival following myocardial infarction

2009 ◽  
Vol 296 (1) ◽  
pp. R1-R8 ◽  
Author(s):  
Timothy E. Lindley ◽  
David W. Infanger ◽  
Mark Rishniw ◽  
Yi Zhou ◽  
Marc F. Doobay ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Central Nervous System ◽  
Nervous System ◽  
Gene Transfer ◽  
Cardiac Function ◽  
Myocardial Function ◽  
Critical Role ◽  
Coronary Artery Ligation ◽  
Control Vector

Dysregulation in central nervous system (CNS) signaling that results in chronic sympathetic hyperactivity is now recognized to play a critical role in the pathogenesis of heart failure (HF) following myocardial infarction (MI). We recently demonstrated that adenovirus-mediated gene transfer of cytoplasmic superoxide dismutase (Ad-Cu/ZnSOD) to forebrain circumventricular organs, unique sensory structures that lack a blood-brain barrier and link peripheral blood-borne signals to central nervous system cardiovascular circuits, inhibits both the MI-induced activation of these central signaling pathways and the accompanying sympathoexcitation. Here, we tested the hypothesis that this forebrain-targeted reduction in oxidative stress translates into amelioration of the post-MI decline in myocardial function and increase in mortality. Adult C57BL/6 mice underwent left coronary artery ligation or sham surgery along with forebrain-targeted gene transfer of Ad-Cu/ZnSOD or a control vector. The results demonstrate marked MI-induced increases in superoxide radical formation in one of these forebrain regions, the subfornical organ (SFO). Ad-Cu/ZnSOD targeted to this region abolished the increased superoxide levels and led to significantly improved myocardial function compared with control vector-treated mice. This was accompanied by diminished levels of cardiomyocyte apoptosis in the Ad-Cu/ZnSOD but not the control vector-treated group. These effects of superoxide scavenging with Ad-Cu/ZnSOD in the forebrain paralleled increased post-MI survival rates compared with controls. This suggests that oxidative stress in the SFO plays a critical role in the deterioration of cardiac function following MI and underscores the promise of CNS-targeted antioxidant therapy for the treatment of MI-induced HF.

scholarly journals Takotsubo syndrome: a way to reach a straightforward diagnosis

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
A Bonanni ◽  
D Pedicino ◽  
R Vinci ◽  
A D'Aiello ◽  
M Ponzo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Myocardial Infarction ◽  
Mononuclear Cells ◽  
Current Knowledge ◽  
Intercellular Adhesion Molecule ◽  
Diagnostic Tools ◽  
Takotsubo Syndrome ◽  
Biological Profile ◽  
Long Term Outcome

Abstract Background/Introduction Acute stress-induced cardiomyopathy, also known as Takotsubo Syndrome (TTS), was originally classified as a benign disease. Nowadays, this assumption has changed, especially in its long-term outcome, due to TTS clinical presentation, that often mirrors the acute myocardial infarction (MI) phenotype. Current knowledge already delineate clinical features distinctive of TTS and MI patients, however, diagnosis requires multiple, expansive, and invasive medical examinations. Moreover, concerning the biological panorama, very slight is known and the lack of a tailored therapy is resented. Therefore, a biological profile for this clinical category could provide easier and less invasive diagnostic tools, leading edge towards novel therapeutic pathways. Purpose The aim of the study is to perform a biological profile of the TTS group compared to the ST Segment Elevation Myocardial Infarction (STEMI) in order to explore the molecular peculiarities attendant the pathophysiologic mechanisms. Methods We performed a gene expression array on two groups of pooled cDNA from peripheral blood mononuclear cells, from TTS (n=11) and STEMI (n=19) patients. We conducted gene expression validations for each enrolled patient through qPCR. Results Our preliminary data displayed several differences in gene expression levels of a grand number of cell adhesion signaling molecule between the two groups. As shown in figure 1, three gene were more expressed in TTS group: Nitric Oxide Synthase 3, also known as endothelial NOS (NOS3; p=0.002), Superoxide dismutase 1 (SOD1; p=0.03) and transferrin receptor (TFRC; p=0.005). Meanwhile, five gene displayed a higher expression in STEMI patients compared to TTS: phospholipase A2 Group 7 (PLA2G7; p=0.04), Galectin 8 (LGALS8; p=0.02), Intercellular Adhesion Molecule 1 (ICAM1; p=0.002), Hyaluronidase 2 (HYAL2; p=0.01) and Hyaluronan Receptor (CD44; p=0.0002). Conclusions The earliest results of this study led us to focus on fewer genes related to endothelial and oxidative stress pathways. TTS is habitually triggered by intense emotional or physical stress. Indeed, our results showed how TTS patients present higher expression of NOS3, SOD1 and TFRC, all components involved in the oxidative stress pathways. In STEMI patients, top expressed genes, such as HYAL2, CD44 and ICAM1, are all associated with extracellular matrix turnover, likely due to the presence of a stenotic plaque and the consequent endothelial derangement. The uncovering of diagnostic biomarkers in TTS might improve the early, non-invasive, stratification of this group of patients, thus facilitating novel and personalized therapeutics design. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The present study was supported by the Italian National Project Grant PRIN 2017.

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